The coisogenic mouse strains C57BL/6 (B/6) and B.C-H-2bm12 (bm12) differ only at the I-A locus. Recognition of the mutant bm12 I-A B/6 cells (and vice versa) results in a chronic graft-versus-host (GVH) reaction that produces a syndrome that closely resembles spontaneous systemic lupus erythematosus (SLE). The use of these I-A coisogenic strains will allow testing of the theory that altered perception of Ia determinants may be a fundamental etiological factor in spontaneous SLE (8), and will permit detailed analysis of mechanisms of autoantibody production. The following areas will be investigated: 1) The role of T cells in the autoimmune-GVH disease. Alloreactive T-cell clones will be used to determine if T cell help for autoantibody production is nonspecific (allogeneic effect), or if it is directed at particular non-MHC autoantigens plus alloantigen. 2) The role of B cells. Autoantibody production hy host or donor B cells and autoantibody isotype will be determined by use of allotype congenic strains and monoclonal anti-allotype and anti-isotype reagents. This will provide clues to mechanisms of T-B collaboration necessary for autoantibody production. In addition, similar approaches will be used to gauge the heterogeneity (i.e., clonality) of different autoantibody responses. 3) The role of immunoregulation. Certain autoantibody specificities (such as Coombs and anti-chromatin) appear to be downregulated after initial induction in the autoimmune-GVH syndrome. Potential mechanisms for this downregulation, including donor B-cell takeover, donor T-cell depletion, and host anti-idiotype or anti-(T cell) clonotype reactivity, will be investigated. These approaches will yield fundamental information regarding potential mechanisms of autoantibody production and will thereby provide insights for the further study of such processes in spontaneous autoimmune diseases.